X Chromosome

• 22 May 2024

Source: TH

Why in News?

Recent genomic studies have uncovered the significant role of the X chromosome in various biological processes and diseases, particularly autoimmune diseases and Alzheimer’s disease.

What is the X Chromosome?

• About: The X chromosome is one of the two sex chromosomes found in humans and many other organisms. It plays a crucial role in sex determination and carries genes essential for various bodily functions.
• Sex Determination: Females typically have two X chromosomes (XX), while males have one X and one Y chromosome (XY).
  • The presence or absence of the Y chromosome determines biological sex.
• Genes and Functions: The X chromosome encodes approximately 800 genes that code for proteins involved in diverse biological functions.
  • Loss of function of these genes can lead to a variety of genetic diseases, which can be broadly classified into three categories:
    • X-linked genetic diseases.
    • Diseases influenced by X-chromosome inactivation (XCI) escape.
    • Diseases linked to X-chromosome aneuploidies.
• X-Linked Genetic Diseases: It results from mutations in genes on the X chromosome.
  • Males, having only one X chromosome, are more likely to express the mutations and develop the disease.
  • Females, with two X chromosomes, have a better chance of having a healthy copy of the gene to offset a mutated one, reducing their risk of developing the full disease.
  • Examples: Red-green colorblindness (affecting around 8% of males).
    • Duchenne muscular dystrophy (1 in every 3,500-5,000 boys born in India) and Agammaglobulinemia (1 in 200,000 live births).
• X-Chromosome Aneuploidies: Numerical aneuploidies of the X chromosome can cause certain diseases.
  • Aneuploidy is a genetic condition where an organism has an abnormal number of chromosomes in its cells.
    • Human cells typically have 46 chromosomes, 23 from each parent. In aneuploidy, a cell may have an extra copy of a chromosome (trisomy) or a missing copy (monosomy).
  • Examples:
    • Klinefelter syndrome (characterised by an extra X chromosome, XXY).
    • Turner syndrome (loss of one X chromosome in females, X instead of XX).
• X-chromosome inactivation (XCI) Escape: In females with two X chromosomes, one X chromosome is randomly inactivated in each cell (except for egg cells) to prevent an imbalance of X-linked genes. This process is called X-inactivation or lyonization.
  • Issues like incomplete inactivation (escape) or skewed inactivation can lead to abnormal gene expression, contributing to X-linked disorders, certain cancers, and autoimmune conditions.
  • The molecular mechanisms behind XCI were discovered in the 1990s, involving two non-coding RNAs called Xist and Tsix.
    • Xist coats and inactivates one of the X chromosomes, while Tsix (reverse of Xist) regulates this process.
  • Recent research has shown that up to a quarter of genes on the X chromosome can escape inactivation and be expressed, even after the XCI process.

How is XCI Linked to Autoimmune Diseases?

• Autoimmune diseases, such as systemic lupus erythematosus, rheumatoid arthritis, and Sjögren's syndrome, are more common in females than males.
• A recent study found that changing the activity of a gene Xist reactivated other inactive genes on the X chromosome.
  • This caused immune system changes that led to lupus-like symptoms, such as increased autoantibodies and inflammation.
• The findings suggest a link between these gene changes and autoimmune diseases, offering hope for new treatments.

Note

Autoimmune diseases occur when the body's immune system mistakenly attacks healthy cells as if they were foreign organisms.

How is the X Chromosome Linked to Alzheimer's Disease?

• Alzheimer's disease exhibits a sex bias, with women having a higher risk compared to men.
  • A study suggests that the gene USP11, involved in protein modification, escapes X inactivation and is expressed more in females.
  • Increased expression of USP11 encourages the accumulation of tau protein in the brain, contributing to the development of Alzheimer's disease.
• This opens new avenues for developing targeted treatments for Alzheimer's disease.